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. 2023 May 31;10(7):ofad277.
doi: 10.1093/ofid/ofad277. eCollection 2023 Jul.

Long COVID Clinical Phenotypes up to 6 Months After Infection Identified by Latent Class Analysis of Self-Reported Symptoms

Michael Gottlieb  1 , Erica S Spatz  2   3   4 , Huihui Yu  2   4 , Lauren E Wisk  5 , Joann G Elmore  5 , Nicole L Gentile  6 , Mandy Hill  7 , Ryan M Huebinger  7 , Ahamed H Idris  8 , Efrat R Kean  9 , Katherine Koo  10 , Shu-Xia Li  4 , Samuel McDonald  8   11 , Juan Carlos C Montoy  12 , Graham Nichol  13 , Kelli N O'Laughlin  14 , Ian D Plumb  15 , Kristin L Rising  9   16 , Michelle Santangelo  10 , Sharon Saydah  15 , Ralph C Wang  12 , Arjun Venkatesh  4   17 , Kari A Stephens  18 , Robert A Weinstein  19   20   21 ; INSPIRE Group
Collaborators, Affiliations

Long COVID Clinical Phenotypes up to 6 Months After Infection Identified by Latent Class Analysis of Self-Reported Symptoms

Michael Gottlieb et al. Open Forum Infect Dis. .

Abstract

Background: The prevalence, incidence, and interrelationships of persistent symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection vary. There are limited data on specific phenotypes of persistent symptoms. Using latent class analysis (LCA) modeling, we sought to identify whether specific phenotypes of COVID-19 were present 3 months and 6 months post-infection.

Methods: This was a multicenter study of symptomatic adults tested for SARS-CoV-2 with prospectively collected data on general symptoms and fatigue-related symptoms up to 6 months postdiagnosis. Using LCA, we identified symptomatically homogenous groups among COVID-positive and COVID-negative participants at each time period for both general and fatigue-related symptoms.

Results: Among 5963 baseline participants (4504 COVID-positive and 1459 COVID-negative), 4056 had 3-month and 2856 had 6-month data at the time of analysis. We identified 4 distinct phenotypes of post-COVID conditions (PCCs) at 3 and 6 months for both general and fatigue-related symptoms; minimal-symptom groups represented 70% of participants at 3 and 6 months. When compared with the COVID-negative cohort, COVID-positive participants had higher occurrence of loss of taste/smell and cognition problems. There was substantial class-switching over time; those in 1 symptom class at 3 months were equally likely to remain or enter a new phenotype at 6 months.

Conclusions: We identified distinct classes of PCC phenotypes for general and fatigue-related symptoms. Most participants had minimal or no symptoms at 3 and 6 months of follow-up. Significant proportions of participants changed symptom groups over time, suggesting that symptoms present during the acute illness may differ from prolonged symptoms and that PCCs may have a more dynamic nature than previously recognized. Clinical Trials Registration. NCT04610515.

Keywords: COVID-19; Long COVID; SARS-CoV-2; cluster; phenotype.

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Conflict of interest statement

Potential conflicts of interest. M. G. reports funding from the Rush Center for Emerging Infectious Diseases Research Grant, Emergency Medicine Foundation/Council of Residency Directors in Emergency Medicine Education Research Grant, Emergency Medicine: Reviews and Perspectives Medical Education Research Grant, University of Ottawa Department of Medicine Education Grant, and Society of Directors of Research in Medical Education Grant. E. S. S. receives grant funding from the National Institute on Minority Health and Health Disparities (U54MD010711-01), the US Food and Drug Administration to support projects within the Yale-Mayo Clinic Center of Excellence in Regulatory Science and Innovation (CERSI, U01FD005938), the National Institute of Biomedical Imaging and Bioengineering (R01EB028106-01), and the National Heart, Lung, and Blood Institute (R01HL151240). J. G. E. reports serving as Editor-in-Chief of Adult Primary Care topics for UpToDate. N. L. G. receives grant funding from the CDC (BAA75D301-20-75D30121C10207). A. V. reports funding for COVID-19–related studies from the Society of Academic Emergency Medicine Foundation Emerging Infectious Disease and Preparedness Grant, the Agency for Healthcare Research and Quality (R01 HS 28340-01), the Food and Drug Administration (ID: 75F40120C00174), and the Centers for Medicare and Medicaid Services. G. N. reports the following: funding for COVID-19–related studies from the National Institute of Allergy and Infectious Diseases (NIAID) (1R01AI66967), research funding from Abiomed, Vapotherm, and ZOLL Medical; consultant to CPR Therapeutics, Heartbeam Inc, Invero Health LLC, Kestra Medical Technologies, Orixha, and ZOLL Circulation; and reports a patent (Method for non-imaging ultrasound to measure blood flow during CPR) and nonprovisional patent (Method for modifying cell injury associated with reduced blood flow). K. N. O. reports funding for COVID-19–related studies from NIAID (1R01AI66967). K. L. R. reports funding for COVID-19–related studies from NIAID (1R01AI66967) and the Philadelphia Department of Public Health. All other authors report no potential conflicts.

Figures

Figure 1.
Figure 1.
Diagrams illustrating latent class analysis models using COVID-19 general (A) and fatigue (B) symptoms. C, Summary of the best-fit latent class analysis models.
Figure 2.
Figure 2.
Participant flow diagram. *Participants who had received their index coronavirus disease 2019 (COVID-19) test >42 days before enrollment or did not have any clinical or pharmacy portals available were ineligible for enrollment.
Figure 3.
Figure 3.
A, Model-estimated class-specific probabilities of general (A) and fatigue (B) symptoms at the acute, 3-month, and 6-month stages for both COVID-positive and COVID-negative participants. Line thickness reflects number of patients in a given class. Abbreviations: Acute, acute stage; 3/6 months: 3 or 6 months; HEENT, head/ears/eyes/nose/throat; minimal-symptoms: minimal number of symptoms in the acute stage; minimal-fatigue, minimal number of fatigue symptoms; maximal-fatigue, maximal number of fatigue symptoms.
Figure 4.
Figure 4.
A–D, Class shifts across time periods for general symptoms among the COVID-positive (A) and COVID-negative (C) groups and for fatigue symptoms among the COVID-positive (B) and COVID-negative (D) groups. Abbreviations: HEENT, head/ears/eyes/nose/throat without loss of smell and taste; maximal-fatigue, maximal number of fatigue symptoms; minimal-fatigue, minimal number of fatigue symptoms; minimal-symptoms, minimal number of symptoms; MSMS, many symptoms across multiple systems.
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References

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